Related Experiment Videos
Design strategies in multiple sclerosis clinical trials. The Cyclosporine Multiple Sclerosis Study Group
G W Ellison1, L W Myers, B D Leake
1Department of Neurology, School of Medicine, University of California, Los Angeles.
Abstract:
After analyzing our natural history data on the course of multiple sclerosis (MS) in more than 500 patients followed for 20 years and our experience in several therapeutic trials, we concluded that a phase III (full) trial for efficacy should have certain properties. For a power of 0.8, alpha of 0.05, and attrition rate of 10% per year, we think the trial should have a minimum sample size of 130 (65 in each arm; placebo versus active) if the design is based upon the proportion of subjects worsening by clinical measures. No stratification by entry Extended Disability Status Scale score is needed if worsening is defined as a change of 1.0 units (2 to 0.5 steps) maintained for 90 days for an entry score of 1 to 5.0 units; or 0.5 units (1 to 0.5 steps) if the entry score is 5.5 to 7 units. We need not stratify by course (relapsing-remitting versus relapsing-progressive) but are less certain about progression from the onset. No run-in period is required to define "activity." Minimum time for treatment is 3 years. We review the justification for our conclusions; modifications in sample size that are necessary if survival analysis is used; impact of the interferon-beta trial (future trials will have an "active" control); and alternative strategies possible if magnetic resonance imaging serves as the primary outcome.
Insights
Designing effective multiple sclerosis (MS) clinical trials requires specific parameters. A minimum sample size of 130 patients is recommended for phase III efficacy studies, with a 3-year treatment duration.
Area of Science:
- Neurology
- Clinical Trial Design
- Multiple Sclerosis Research
Background:
- Analysis of natural history data from over 500 multiple sclerosis (MS) patients over 20 years.
- Experience from multiple therapeutic trials informs optimal study design.
Purpose of the Study:
- To define essential properties for phase III multiple sclerosis (MS) efficacy trials.
- To establish minimum sample size and design considerations based on clinical measures of worsening.
Main Methods:
- Statistical power of 0.8 and alpha of 0.05 with a 10% annual attrition rate.
- Analysis based on the proportion of subjects worsening, using specific Extended Disability Status Scale (EDSS) score changes.
- Evaluation of stratification needs and treatment duration.
Main Results:
- Minimum sample size of 130 patients (65 per arm) recommended for efficacy trials.
- No stratification by entry EDSS score needed for specific worsening definitions.
- No run-in period required; minimum treatment time of 3 years.
Conclusions:
- Phase III MS trials require a minimum of 130 patients and 3 years of treatment.
- Specific criteria for defining patient worsening simplify trial design.
- Future trials may incorporate active controls and magnetic resonance imaging (MRI) outcomes.